Endotheliopathy in COVID-19-associated coagulopathy: evidence from a single-centre, cross-sectional study

Abstract

Background: An important feature of severe acute respiratory syndrome coronavirus 2 pathogenesis is COVID-19-associated coagulopathy, characterised by increased thrombotic and microvascular complications. Previous studies have suggested a role for endothelial cell injury in COVID-19-associated coagulopathy. To determine whether endotheliopathy is involved in COVID-19-associated coagulopathy pathogenesis, we assessed markers of endothelial cell and platelet activation in critically and non-critically ill patients admitted to the hospital with COVID-19.

Methods: In this single-centre cross-sectional study, hospitalised adult (≥18 years) patients with laboratory-confirmed COVID-19 were identified in the medical intensive care unit (ICU) or a specialised non-ICU COVID-19 floor in our hospital. Asymptomatic, non-hospitalised controls were recruited as a comparator group for biomarkers that did not have a reference range. We assessed markers of endothelial cell and platelet activation, including von Willebrand Factor (VWF) antigen, soluble thrombomodulin, soluble P-selectin, and soluble CD40 ligand, as well as coagulation factors, endogenous anticoagulants, and fibrinolytic enzymes. We compared the level of each marker in ICU patients, non-ICU patients, and controls, where applicable. We assessed correlations between these laboratory results with clinical outcomes, including hospital discharge and mortality. Kaplan-Meier analysis was used to further explore the association between biochemical markers and survival.

Findings: 68 patients with COVID-19 were included in the study from April 13 to April 24, 2020, including 48 ICU and 20 non-ICU patients, as well as 13 non-hospitalised, asymptomatic controls. Markers of endothelial cell and platelet activation were significantly elevated in ICU patients compared with non-ICU patients, including VWF antigen (mean 565% [SD 199] in ICU patients vs 278% [133] in non-ICU patients; p<0·0001) and soluble P-selectin (15·9 ng/mL [4·8] vs 11·2 ng/mL [3·1]; p=0·0014). VWF antigen concentrations were also elevated above the normal range in 16 (80%) of 20 non-ICU patients. We found mortality to be significantly correlated with VWF antigen (r = 0·38; p=0·0022) and soluble thrombomodulin (r = 0·38; p=0·0078) among all patients. In all patients, soluble thrombomodulin concentrations greater than 3·26 ng/mL were associated with lower rates of hospital discharge (22 [88%] of 25 patients with low concentrations vs 13 [52%] of 25 patients with high concentrations; p=0·0050) and lower likelihood of survival on Kaplan-Meier analysis (hazard ratio 5·9, 95% CI 1·9-18·4; p=0·0087).

Interpretation: Our findings show that endotheliopathy is present in COVID-19 and is likely to be associated with critical illness and death. Early identification of endotheliopathy and strategies to mitigate its progression might improve outcomes in COVID-19.

Funding: This work was supported by a gift donation from Jack Levin to the Benign Hematology programme at Yale, and the National Institutes of Health.

Figure 1

Comparisons of select haemostatic factors in ICU vs non-ICU patients Datapoints indicate individual measurements, whereas horizontal bars show mean (SD) for α₂-antiplasmin, VWF antigen, and factor VIII and median (IQR) for PAI-1, D-dimer, TAT, and VWF activity. Green shaded areas indicate the normal range of values. ICU=intensive care unit. ULN=upper limit of normal. LLN=lower limit of normal. FEU=fibrinogen equivalent units. PAI-1=plasminogen activator inhibitor-1. TAT=thrombin-antithrombin complexes. VWF=von Willebrand factor. *Thick horizontal bar denotes patients who had measurements above the limit of detection of the assay.

Figure 2

Comparisons of endothelial cell and platelet activation markers in ICU patients, non-ICU patients, and controls Datapoints indicate individual measurements, whereas horizontal bars show mean (SD) for soluble P-selectin and median (IQR) for sCD40L and soluble thrombomodulin. ICU=intensive care unit. sCD40L=soluble CD40 ligand.

Figure 3

Kaplan–Meier curve of survival and soluble thrombomodulin concentration Data are shown for patients with low soluble thrombomodulin (<3·26 ng/mL) and high soluble thrombomodulin (>3·26 ng/mL). Shaded areas represent 95% CIs. ICU=intensive care unit.